This proposal will investigate mechanisms of antibody-dependent cellular cytotoxicity (ADCC) and activated macrophage cytolysis. Both red blood cells (RBC) and tumor targets will be studied with toxicity quantitated by release of 51Cr (chromium) or radiolabel from DNA. Various mouse peritoneal preparations and cloned marcophage cell lines known to differ in ability to mediate ADCC to RBC, ADCC to tumor targets and nonspecific activation to tumor lysis will be utilized to characterize physiological differences among subgroups of mononuclear phagocytes. The requirement for T or B lymphocyte participation in activation by microbial products will be tested in vitro. Existing models of activation by soluble factors derived from stimulated spleen cells will be used to study the role of the cell's physiology in this process. Metabolic and esterase inhibitors which we have shown to augment ADCC and other agents specifically blocking lysis but not target phagocytosis will be used to analyze the lytic mechanism. The effect of physical parameters such as temperature and type of assay vessel known to drastically alter the ratio of lysis to phagocytosis will be investigated to understand how macrophage effector functions can be modulated. Cell line macrophages will be synchonized to study cell cycle dependency for activation and effector functions. Antibody preparations of individual immunoglobulin heavy chain classes including monoclonal hybridoma antibody will be prepared to determine the function of class in directing ADCC or blocking macrophage toxicity. The overall emphasis of this proposal is on the physiology, heterogeneity and regulation of macrophage effector activity, rather than on characterization of lymphocyte stimulating factors or classes of susceptible and resistant targets.